Patients aged less than 40 years with a new diagnosis of high-grade osteosarcoma and a poor response to preoperative chemotherapy do not benefit from additional postoperative ifosfamide and etoposide

medwireNews: EURAMOS-1 trial results do not support the addition of high-dose ifosfamide and etoposide (MAPIE) to postoperative cisplatin, doxorubicin and methotrexate (MAP) chemotherapy for patients aged less than 40 years with a new diagnosis of high-grade osteosarcoma and a poor response to preoperative chemotherapy.

“This study is both timely and important because it provides crucial information for oncologists on how to approach the care of paediatric, adolescent, and young adult patients with osteosarcoma who have responded poorly to preoperative chemotherapy”, writes Eugenie Kleinerman, from the University of Texas MD Anderson Cancer Center in Houston, USA, in an accompanying comment published in The Lancet Oncology.

After a median of 62.1 months, the primary outcome of event-free survival in the phase III trial for patients with at least 10% viable tumour after preoperative chemotherapy was similar in the 308 patients randomly assigned to receive MAPIE with mesna uroprotection and the 308 patients given MAP, with a nonsignificant hazard ratio (HR) of 0.98.

Three-year event-free survival was achieved by 53% and 55% of the MAPIE and MAP treatment groups, respectively, with comparable rates also found when separately assessing patients with baseline localised disease (57 vs 60%) and metastatic disease (18 vs 24%).

Overall survival at 3 years was reported for 77% and 72% of the MAPIE and MAP groups, respectively, and while data are yet to mature, the current estimation is a nonsignificant HR of 0.97, say Matthew Sydes, from University College London in the UK, and co-investigators.

"Chemotherapy compliance was generally poorer with MAPIE than with MAP", the team notes, with MAPIE patients being less likely to receive the target number of doses of the three MAP agents or receive 80% of their planned doses.

Grade 3 or more severe toxicity of any type was reported in 94% of the 298 MAPIE-treated patients and 95% of the 301 patients given MAP. But the addition of ifosfamide and etoposide was associated with significantly higher rates of nonhaematological toxicity of both grade 3 and above (87 vs 77%) and grade 4 (24 vs 12%).

As expected, there was a trend towards a higher rate of secondary malignancies in patients given MAPIE, with 10 events reported versus three in the MAP arm. Although this difference did not reach significance, the authors emphasize that "continued follow-up is crucial to identify any second solid malignancies occurring as later events in this patient population."

Summarising the EURAMOS-1 results, the investigators "argue strongly against adding ifosfamide and etoposide to the backbone of MAP therapy for patients whose tumour shows a poor response to preoperative treatment."

Eugenie Kleinerman agrees that alternative strategies should now be considered for this patient population.

“The success of mifamurtide shows that osteosarcoma is sensitive to immunotherapy, suggesting that this should be the focus for future international trials”, she suggests.